This project is directed at understanding the role of specific enzyme systems in generating and maintaining host immunity. The approach taken involves the creation of mice with discrete defects in host defenses by using homologous recombination of DNA into the host genome to disrupt relevant genes. We have manipulated the NADPH oxidase system to create mice with a genetic defect similar to one found in humans, chronic granulomatous disease (CGD). This project relies upon a thorough understanding of the molecular and functional organization of the NADPH oxidase system and the mutations which disable it. We have created a mouse deficient in the p47phox gene product, a necessary component of the NADPH oxidase complex. In the absence of this gene product, mice, like humans, fail to produce phagocyte superoxide and metabolites. In addition, these mice show a benefit to the administration of prophylactic interferon gamma in terms of the prevention of infections. Therefore, this mouse system presents a model in which to investigate interferon gamma~s effect and mechanism of action in infection prophylaxis. Creation of a mouse model of CGD has provided us with the opportunity to investigate specific mechanisms, interventions, and therapies, including interferon gamma and gene therapy. Since the NADPH oxidase has been implicated the genesis of other conditions, such as atherosclerosis and reperfusion injury, this mouse will provide a valuable tool for the determination of its contribution in these settings as well.